The purpose of this study was to compare tomosynthesis with radiography for the detection of bone erosions of the foot in patients with established rheumatoid arthritis (RA) using MDCT as a reference ... [more ▼]

The purpose of this study was to compare tomosynthesis with radiography for the detection of bone erosions of the foot in patients with established rheumatoid arthritis (RA) using MDCT as a reference standard. [less ▲]

OBJECTIVE: Knee osteoarthritis (OA) is a heterogeneous, complex joint pathology of unknown aetiology. Biomarkers have been widely used to investigate OA but currently available biomarkers lack specificity ... [more ▼]

OBJECTIVE: Knee osteoarthritis (OA) is a heterogeneous, complex joint pathology of unknown aetiology. Biomarkers have been widely used to investigate OA but currently available biomarkers lack specificity and sensitivity. Therefore, novel biomarkers are needed to better understand the pathophysiological processes of OA initiation and progression. METHODS: Surface enhanced laser desorption/ionisation-time of flight-mass spectrometry proteomic technique was used to analyse protein expression levels in 284 serum samples from patients with knee OA classified according to Kellgren and Lawrence (K&L) score (0-4). OA serum samples were also compared to serum samples provided by healthy individuals (negative control subjects; NC; n=36) and rheumatoid arthritis (RA) patients (n=25). Proteins that gave similar signal in all K&L groups of OA patients were ignored, whereas proteins with increased or decreased levels of expression were selected for further studies. RESULTS: Two proteins were found to be expressed at higher levels in sera of OA patients at all four K&L scores compared to NC and RA, and were identified as V65 vitronectin fragment and C3fpeptide. Of the two remaining proteins, one showed increased expression (unknown protein at m/z of 3762) and the other (identified as connective tissue-activating peptide III protein) was decreased in K&L scores >2 subsets compared to NC, RA and K&L scores 0 or 1 subsets. CONCLUSION: The authors detected four unexpected biomarkers (V65 vitronectin fragment, C3f peptide, CTAP-III and m/z 3762 protein) that could be relevant in the pathophysiological process of OA as having significant correlation with parameters reflecting local inflammation and bone remodelling, as well as decrease in cartilage turnover. [less ▲]

Clinical proteomics is a technical approach studying the entire proteome expressed by cells, tissues or organs. It describes the dynamics of cell regulation by detecting molecular events related to ... [more ▼]

Clinical proteomics is a technical approach studying the entire proteome expressed by cells, tissues or organs. It describes the dynamics of cell regulation by detecting molecular events related to diseases development. Proteomic techniques focus mainly on identification of new biomarkers or new therapeutic targets. It is a multidisciplinary approach using medical, biological, bioanalytical and bioinformatics knowledges. A strong collaboration between these fields allowed SELDI-TOF-MS proteomics studies to be performed at the CHU and the University of Liege, in GIGA-Research facilities. The aim of these studies was driven along three main axes of research related to the identification of biomarkers specific to a studied pathology, to a common biological pathway and, finally, to a treatment response. [less ▲]

Systemic inflammatory response syndrome (SIRS) can be related to acute inflammatory conditions that can be sometimes missed and inappropriately managed as severe infections. We report a case of Churg ... [more ▼]

Systemic inflammatory response syndrome (SIRS) can be related to acute inflammatory conditions that can be sometimes missed and inappropriately managed as severe infections. We report a case of Churg Strauss Syndrome (CSS), presenting as septic shock with acute onset of fever and multiple organ failure including pulmonary involvement with severe hypoxemia, hypotension requiring vasoactive support and acute renal failure. Antibiotics were discontinued and intravenous steroids allowed a rapid clinical improvement in close relationship with the fall in circulating eosinophils count. [less ▲]

BACKGROUND: SELDI-TOF mass spectrometry (MS) is a high-throughput proteomic approach with potential for identifying novel forms of serum biomarkers of arthritis. METHODS: We used SELDI-TOF MS to analyze serum samples from patients with various forms of inflammatory arthritis. Several protein profiles were collected on different Bio-Rad Laboratories ProteinChip arrays (CM10 and IMAC-Cu(2+)) and were evaluated statistically to select potential biomarkers. RESULTS: SELDI-TOF MS analyses identified several calgranulin proteins [S100A8 (calgranulin A), S100A9 (calgranulin B), S100A9*, and S100A12 (calgranulin C)], serum amyloid A (SAA), SAA des-Arg (SAA-R), and SAA des-Arg/des-Ser (SAA-RS) as biomarkers and confirmed the results with other techniques, such as western blotting, immunoprecipitation, and nano-LC-MS/MS. The S100 proteins were all able to significantly differentiate samples from patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) from those of patients with inflammatory bowel diseases used as an inflammatory control (IC) group, whereas the SAA, SAA-R, and SAA-RS proteins were not, with the exception of AS. The 4 S100 proteins were coproduced in all of the pathologies and were significantly correlated with the plasma calprotectin concentration; however, these S100 proteins were correlated with the SAA peak intensities only in the RA and IC patient groups. In RA, these S100 proteins (except for S100A12) were significantly correlated with the serum concentrations of C-reactive protein, matrix metalloproteinase 3, and anti-cyclic citrullinated peptide and with the Disease Activity Score (DAS(28)). CONCLUSIONS: The SELDI-TOF MS technology is a powerful approach for analyzing the status of monomeric, truncated, or posttranslationally modified forms of arthritis biomarkers, such as the S100A8, S100A9, S100A12, and SAA proteins. The fact that the SELDI-TOF MS data were correlated with results obtained with the classic calprotectin ELISA test supports the reliability of this new proteomic technique. [less ▲]

BACKGROUND: In drug-induced toxic epidermal necrolysis (TEN), the epidermal destruction is associated with a slight to moderate lymphomonocytic cell infiltrate. Interleukin (IL)-8, which is a keratinocyte ... [more ▼]

BACKGROUND: In drug-induced toxic epidermal necrolysis (TEN), the epidermal destruction is associated with a slight to moderate lymphomonocytic cell infiltrate. Interleukin (IL)-8, which is a keratinocyte-derived pro-inflammatory cytokine, might be involved in this process. The IL-8 receptor CXCR2 has also been shown to be overexpressed in some epidermal disorders. METHODS: IL-8 concentration was measured by ELISA in both serum and blister fluid from 10 patients with TEN. Data were compared with similar dosages performed in 15 cases of second-degree burn and 7 cases of bullous pemphigoid (BP). CXCR2 expression on keratinocytes was studied using immunohistochemistry on skin biopsies performed in TEN bullous lesions and clinically uninvolved skin of the same patients. RESULTS: IL-8 was significantly overexpressed in TEN blister fluid compared with TEN serum (P = 0.0015). However, no difference was found in IL-8 concentrations present in blister fluid of TEN, second-degree burn and BP. CXCR2 was moderately expressed in the epidermis of some TEN blisters, but was never expressed in clinically uninvolved skin. CXCR2 expression was not found in the follicular epidermal root sheaths of patients with TEN. CONCLUSIONS: These results indicate that abundant IL-8 appears to be locally produced in TEN epidermis, but this overexpression is not disease-specific. Because of the paucity of the inflammatory infiltrate in TEN, it is unlikely that IL-8 induces epidermal destruction through its chemotactic activity. Moreover, the complete absence of neutrophils in TEN lesions indicates that the major chemotactic effect of IL-8 on neutrophils is not operative in TEN skin. This implies that IL-8 activates different functions according to the local environment. CXCR2 expression on TEN keratinocytes is expressed on some necrotic keratinocytes, consistent with a discrete IL-8 proapoptotic activity. The lack of CXCR2 expression in the follicular root sheaths argues against a role for IL-8 in TEN epidermal repair. [less ▲]

in European Journal of Nuclear Medicine and Molecular Imaging (2006), 33(3), 275-280

Purpose: The aim of this study was to assess rheumatoid arthritis (RA) synovitis with positron emission tomography (PET) and F-18-fluorodeoxyglucose (F-18-FDG) in comparison with dynamic magnetic ... [more ▼]

Purpose: The aim of this study was to assess rheumatoid arthritis (RA) synovitis with positron emission tomography (PET) and F-18-fluorodeoxyglucose (F-18-FDG) in comparison with dynamic magnetic resonance imaging (MRI) and ultrasonography (US). Methods: Sixteen knees in 16 patients with active RA were assessed with PET, MRI and US at baseline and 4 weeks after initiation of anti-TNF-alpha treatment. All studies were performed within 4 days. Visual and semi-quantitative (standardised uptake value, SUV) analyses of the synovial uptake of FDG were performed. The dynamic enhancement rate and the static enhancement were measured after i.v. gadolinium injection and the synovial thickness was measured in the medial, lateral patellar and suprapatellar recesses by US. Serum levels of C-reactive protein (CRP) and metalloproteinase-3 (MMP-3) were also measured. Results: PET was positive in 69% of knees while MRI and US were positive in 69% and 75%. Positivity on one imaging technique was strongly associated with positivity on the other two. PET-positive knees exhibited significantly higher SUVs, higher MRI parameters and greater synovial thickness compared with PET-negative knees, whereas serum CRP and MMP-3 levels were not significantly different. SUVs were significantly correlated with all MRI parameters, with synovial thickness and with serum CRP and MMP-3 levels at baseline. Changes in SUVs after 4 weeks were also correlated with changes in MRI parameters and in serum CRP and MMP-3 levels, but not with changes in synovial thickness. Conclusion: F-18-FDG PET is a unique imaging technique for assessing the metabolic activity of synovitis. The PET findings are correlated with MRI and US assessments of the pannus in RA, as well as with the classical serum parameter of inflammation, CRP, and the synovium-derived parameter, serum MMP-3. Further studies are warranted to establish the place of metabolic imaging of synovitis in RA. [less ▲]

OBJECTIVE: Interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) activation of gp130 represents an alternative pathway for osteoclast development in inflammatory conditions. The goal of the present ... [more ▼]

OBJECTIVE: Interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) activation of gp130 represents an alternative pathway for osteoclast development in inflammatory conditions. The goal of the present study was to investigate changes in sIL-6R levels in response to the inflammatory cytokines IL-1beta and tumor necrosis factor alpha (TNFalpha) and to determine the role of TNFalpha-converting enzyme (TACE) in this process. METHODS: Levels of sIL-6R in the culture media of MG63 and SAOS-2 osteoblast-like cell lines after exposure to various agents were determined by immunoassay. TACE protein levels were measured by Western immunoblotting. Cells were transfected with small interfering RNA (siRNA) or with an expression plasmid for IL-6R and TACE to determine the potential involvement of TACE in IL-6R shedding. RESULTS: IL-1beta and TNFalpha increased the levels of sIL-6R in the culture media of MG63 osteoblast-like cells. This effect was not influenced by cycloheximide or 5,6-dichlorobenzimidazole riboside but was markedly inhibited by the calcium chelator EGTA and by the TACE and matrix metalloproteinase inhibitor hydroxamate (Ru36156). IL-1beta and TNFalpha had no influence on the alternatively spliced form of IL-6R RNA. Levels of sIL-6R were reduced when MG63 cells were transiently transfected with TACE siRNA. Transfection of SAOS-2 cells with expression plasmids for IL-6R and TACE produced a dose-dependent increase in sIL-6R levels. CONCLUSION: IL-1beta- and TNFalpha-mediated induction of IL-6R shedding in osteoblast-like cells is at least partly dependent on TACE activation. [less ▲]

OBJECTIVE: To identify serum protein biomarkers specific for rheumatoid arthritis (RA), using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) technology. METHODS: A total of 103 serum samples from patients and healthy controls were analyzed. Thirty-four of the patients had a diagnosis of RA, based on the American College of Rheumatology criteria. The inflammation control group comprised 20 patients with psoriatic arthritis (PsA), 9 with asthma, and 10 with Crohn's disease. The noninflammation control group comprised 14 patients with knee osteoarthritis and 16 healthy control subjects. Serum protein profiles were obtained by SELDI-TOF-MS and compared in order to identify new biomarkers specific for RA. Data were analyzed by a machine learning algorithm called decision tree boosting, according to different preprocessing steps. RESULTS: The most discriminative mass/charge (m/z) values serving as potential biomarkers for RA were identified on arrays for both patients with RA versus controls and patients with RA versus patients with PsA. From among several candidates, the following peaks were highlighted: m/z values of 2,924 (RA versus controls on H4 arrays), 10,832 and 11,632 (RA versus controls on CM10 arrays), 4,824 (RA versus PsA on H4 arrays), and 4,666 (RA versus PsA on CM10 arrays). Positive results of proteomic analysis were associated with positive results of the anti-cyclic citrullinated peptide test. Our observations suggested that the 10,832 peak could represent myeloid-related protein 8. CONCLUSION: SELDI-TOF-MS technology allows rapid analysis of many serum samples, and use of decision tree boosting analysis as the main statistical method allowed us to propose a pattern of protein peaks specific for RA. [less ▲]

The aim of this study was to assess synovitis by F-18-FDG PET in an individual joint analysis and in a global analysis of rheumatoid arthritis (RA) disease activity and to compare F-18-FDG PET parameters ... [more ▼]

The aim of this study was to assess synovitis by F-18-FDG PET in an individual joint analysis and in a global analysis of rheumatoid arthritis (RA) disease activity and to compare F-18-FDG PET parameters with clinical, biologic, and sonographic (US) rheumatoid parameters. Methods: Three hundred fifty-six joints were assessed in 21 patients with active RA: the knees in all subjects and either wrists as well as metacarpophalangeal and proximal interphalangeal joints in 13 patients, or ankles and the first metatarsophalangeal joints in the remaining 8 patients. PET analysis consisted of a visual identification of F-18-FDG uptake in the synovium and measurements of standardized uptake values (SUVs). Independent assessors performed the clinical and US examinations. Results: PET positivity was found in 63% of joints, whereas 75%, 79%, and 56% were positive for swelling, tenderness, and US analysis, respectively. Both the rate of PET-positive joints and the SUV increased with the number of positive parameters present (swelling, tenderness, US positivity) and with the synovial thickness. The mean SUV was significantly higher in joints where a power Doppler signal was found. In a global PET analysis, the number of PET-positive joints and the cumulative SUV were significantly correlated with the swollen and tender joint counts, the patient and physician global assessments, the erythrocyte sedimentation rate and C-reactive protein serum levels, the disease activity score and the simplified disease activity index, the number of US-positive joints, and the cumulative synovial thickness. Conclusion: F-18-FDG PET is a unique imaging technique that can assess the metabolic activity of synovitis and measure the disease activity in RA. [less ▲]

We have previously shown that nuclear factor-kappaB inhibition by adenovirus expressing mutated IkappaB-alpha or by proteasome inhibitor increases human articular chondrocytes sensibility to apoptosis. Moreover, the nuclear factor-kappaB inhibitor BAY11-7085, a potent anti-inflammatory drug in rat adjuvant arthritis, is itself a proapoptotic agent for chondrocytes. In this work, we show that BAY 11-7085 but not the proteasome inhibitor MG-132 induced a rapid and sustained phosphorylation of extracellular signal-regulated kinases (ERK1/2) in human articular chondrocytes. The level of ERK1/2 phosphorylation correlated with BAY 11-7085 concentration and chondrocyte apoptosis. 15-Deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) and its precursor prostaglandin (PG) D2 but not PGE2 and PGF2alpha rescued chondrocytes from BAY 11-7085-induced apoptosis. 15d-PGJ2 markedly inhibited BAY 11-7085-induced phosphorylation of ERK1/2. BAY 11-7085 also induced ERK1/2 phosphorylation and apoptosis in human synovial fibroblasts, and these reactions were down-regulated by 15d-PGJ2. Further analysis in synovial fibroblasts showed that only molecules that suppressed BAY 11-7085-induced phosphorylation of ERK1/2 (i.e. 15d-PGJ2, PGD2, and to a lesser extent, MEK1/2 inhibitor UO126, but not prostaglandins E2 and F2alpha or peroxisome proliferator-activated receptor-gamma agonist ciglitazone) were able protect cells from apoptosis. These results suggested that the antiapoptotic effect of 15d-PGJ2 on chondrocytes and synovial fibroblasts might involve inhibition of ERK1/2 phosphorylation. [less ▲]

PURPOSE: To evaluate by using B-mode and power Doppler ultrasonography (US) and clinical assessment the response of hand joint synovitis in patients with active rheumatoid arthritis (RA) to treatment with ... [more ▼]

PURPOSE: To evaluate by using B-mode and power Doppler ultrasonography (US) and clinical assessment the response of hand joint synovitis in patients with active rheumatoid arthritis (RA) to treatment with the anti-tumor necrosis factor-alpha agent infliximab. MATERIALS AND METHODS: Wrists, metacarpophalangeal (MCP) joints, and proximal interphalangeal (PIP) joints in 11 patients with active RA were assessed before and 6 weeks after three infliximab infusions. US assessment was performed at a single site in the MCP and PIP joints and at two sites (radiocarpal and intercarpal) in the wrists. Twenty measurements were performed in the wrists; 110 measurements, in the MCP joints; and 103 measurements, in the PIP joints. Two wrists and seven PIP joints were excluded owing to complete joint destruction. US parameters (synovial thickness, number of US-positive joints [ie, with synovial thickness > or = 1 mm], cumulative synovial thickness index, and presence of Doppler signal) and clinical parameters (swollen joint count) were independently assessed and compared with baseline values by using the McNemar chi2 and paired Student t tests. RESULTS: After infliximab treatment, there was a significant decrease in the mean numbers of swollen and US-positive joints and in the cumulative synovial thickness (P <.05). The mean synovial thickness decreased in all joints swollen at baseline and in the MCP and PIP joints not swollen at baseline (P <.01). Change from baseline cumulative synovial thickness correlated significantly with change in disease activity score (r = 0.69, P <.05). The number of positive Doppler US signals decreased significantly (in 13 US-positive joints at baseline, in five after treatment; P <.05). CONCLUSION: US is a feasible imaging modality for measurement of the response of RA small-joint synovitis to therapy. [less ▲]

TNF-alpha plays a key role in rheumatoid arthritis, but its effect on chondrocyte survival is still conflicting. In the present study, we tested how TNF-alpha influences chondrocyte survival in response ... [more ▼]

TNF-alpha plays a key role in rheumatoid arthritis, but its effect on chondrocyte survival is still conflicting. In the present study, we tested how TNF-alpha influences chondrocyte survival in response to nitric oxide (NO)-related apoptotic signals, which are abundant during rheumatoid arthritis. Human primary articular chondrocytes or cartilage explants were pretreated with TNF-alpha for 24 hours and then treated with the proapoptotic NO donor sodium-nitro-prusside (SNP) for an additional 24 hours. TNF-alpha pretreatment markedly protected chondrocytes from SNP-induced cell death. Preincubation of chondrocytes with TNF-alpha inhibited both SNP-induced high-molecular weight DNA fragmentation and annexin V-FITC binding. Of interest, TNF-alpha induced persistent nuclear factor-kappaB (NF-kappaB)-DNA binding activity even in the presence of SNP, mirroring apoptosis protection effects. Both the TNF-alpha antiapoptotic effect and NF-kappaB-DNA binding activity were significantly inhibited by NF-kappaB inhibitors, Bay 11-7085, MG-132, and adenovirus-expressing mutated IkappaB-alpha. Phosphatidylinositol-3 kinase inhibitor LY 294002 also markedly inhibited the antiapoptotic effect of TNF-alpha. In primary chondrocytes, TNF-alpha induced expression of the antiapoptotic protein Cox-2, which persisted in the presence of SNP, and a specific Cox-2 inhibitor significantly blocked the TNF-alpha protective effect. We therefore conclude that TNF-alpha-mediated protection of chondrocytes from NO-induced apoptosis acts through NF-kappaB and requires Cox-2 activity. [less ▲]